Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 14, 2019; 25(2): 220-232
Published online Jan 14, 2019. doi: 10.3748/wjg.v25.i2.220
Six-long non-coding RNA signature predicts recurrence-free survival in hepatocellular carcinoma
Jing-Xian Gu, Xing Zhang, Run-Chen Miao, Xiao-Hong Xiang, Yu-Nong Fu, Jing-Yao Zhang, Chang Liu, Kai Qu
Jing-Xian Gu, Xing Zhang, Run-Chen Miao, Xiao-Hong Xiang, Yu-Nong Fu, Jing-Yao Zhang, Chang Liu, Kai Qu, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
Author contributions: Gu JX and Qu K designed the research; Gu JX, Zhang X, and Miao RC collected and analyzed data; Xiang XH and Fu YN constructed the figures; Gu JX, Zhang JY, Liu C, and Qu K drafted and revised the manuscript.
Supported by The National Natural Science Foundation of China, No. 81773128 and No. 81871998; the Natural Science Basic Research Plan in Shaanxi Province of China, No. 2017JM8039; China Postdoctoral Science Foundation, No. 2018m641000; and Research Fund for Young Star of Science and Technology in Shaanxi Province, No. 2018KJXX-022.
Conflict-of-interest statement: None.
Data sharing statement: The data used in this manuscript are accessible through https://www.ncbi.nlm.nih.gov/geo/ and https://portal.gdc.cancer.gov/.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Kai Qu, PhD, MD, Associated Professor, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China. qukai@xjtu.edu.cn
Telephone: +86-13609117104 Fax: +86-29-85323900
Received: October 10, 2018
Peer-review started: October 12, 2018
First decision: November 15, 2018
Revised: December 5, 2018
Accepted: December 19, 2018
Article in press: December 20, 2018
Published online: January 14, 2019
Abstract
BACKGROUND

Recent evidence shows that long non-coding RNAs (lncRNAs) are closely related to hepatogenesis and a few aggressive features of hepatocellular carcinoma (HCC). Increasing studies demonstrate that lncRNAs are potential prognostic factors for HCC. Moreover, several studies reported the combination of lncRNAs for predicting the overall survival (OS) of HCC, but the results varied. Thus, more effort including more accurate statistical approaches is needed for exploring the prognostic value of lncRNAs in HCC.

AIM

To develop a robust lncRNA signature associated with HCC recurrence to improve prognosis prediction of HCC.

METHODS

Univariate COX regression analysis was performed to screen the lncRNAs significantly associated with recurrence-free survival (RFS) of HCC in GSE76427 for the least absolute shrinkage and selection operator (LASSO) modelling. The established lncRNA signature was validated and developed in The Cancer Genome Atlas (TCGA) series using Kaplan-Meier curves. The expression values of the identified lncRNAs were compared between the tumor and non-tumor tissues. Pathway enrichment of these lncRNAs was conducted based on the significantly co-expressed genes. A prognostic nomogram combining the lncRNA signature and clinical characteristics was constructed.

RESULTS

The lncRNA signature consisted of six lncRNAs: MSC-AS1, POLR2J4, EIF3J-AS1, SERHL, RMST, and PVT1. This risk model was significantly associated with the RFS of HCC in the TCGA cohort with a hazard ratio (HR) being 1.807 (95%CI [confidence interval]: 1.329-2.457) and log-rank P-value being less than 0.001. The best candidates of the six-lncRNA signature were younger male patients with HBV infection in relatively early tumor-stage and better physical condition but with higher preoperative alpha-fetoprotein. All the lncRNAs were significantly upregulated in tumor samples compared to non-tumor samples (P < 0.05). The most significantly enriched pathways of the lncRNAs were TGF-β signaling pathway, cellular apoptosis-associated pathways, etc. The nomogram showed great utility of the lncRNA signature in HCC recurrence risk stratification.

CONCLUSION

We have constructed a six-lncRNA signature for prognosis prediction of HCC. This risk model provides new clinical evidence for the accurate diagnosis and targeted treatment of HCC.

Keywords: Long non-coding RNAs, Hepatocellular carcinoma, Prognostic signature, Recurrence-free survival, Least absolute shrinkage and selection operator

Core tip: In this study, we constructed a six-lncRNA signature that could predict the recurrence-free survival (RFS) of hepatocellular carcinoma (HCC) via a novel formulation method - the least absolute shrinkage and selection operator (LASSO). LASSO, based on penalized regression, can handle all the independent variables simultaneously, which has been demonstrated to be more accurate than stepwise regression. This lncRNA-signature was further validated and developed in another independent dataset from The Cancer Genome Atlas project. Our risk score system showed great utility in predicting the RFS of HCC and provided extra evidence for guiding targeted treatment of HCC.